Glioblastoma (GBM) is a primary malignancy of the central nervous system that is nearly universally fatal. Our long-term goal is to understand the genomic changes that lead to GBM and to use this information to develop better options for GBM patients. Recently, our group has shown that the familial Parkinson's disease (PD) gene, PARK2, is one of the most commonly inactivated tumor suppressors in GBM. The central hypothesis of this application is that inactivation of PARK2 is a critical event underlying the development of a subset of GBMs. We and others have shown that PARK2 is a multisite tumor suppressor, inactivated in a wide range of human cancers. Intriguingly, mutation of PARK2, which encodes a ubiquitin E3 ligase, is also the most frequent cause of hereditary PD. PARK2 potently suppresses tumor cell growth, a property that is abrogated by cancer-specific mutations which we have identified. However, the molecular mechanisms underlying PARK2's tumor suppressive activity are poorly understood. The objective of this proposal is to understand the function of PARK2 in the molecular pathogenesis of GBM by pursuing the following 3 specific aims. In Aim 1, we will elucidate the cellular mechanisms underlying the tumor suppressive activity of PARK2 and its effects on genomic stability. We will systematically characterize the effects of PARK2 loss on cell cycle regulation and chromosomal stability using both in vitro and in vivo approaches. We will determine the phenotypic effects of PARK2 inactivation that develop in conjunction with changes in genomic stability. In Aim 2, we will define the functional role of the PARK2 /FBXW7 regulatory axis in GBM. Both PARK2 and FBXW7 (also called hCDC4) encode ubiquitin E3 ligases and are tumor suppressors mutated in a number of cancer types, including GBM. Preliminary data from our laboratory shows that mutation of either gene results in a loss of the ability to regulate cyclin E levels and mitotic instability. We showed that disruption of these two genes are mutually exclusive in GBM. Furthermore, PARK2 normally interacts with FBXW7. Our hypothesis is that PARK2 and FBXW7 are components of a common pathway regulating cyclin E levels and genetic stability. We will define the tenants of this pathway using a rigorous biochemical and cell biological approach to characterize the functional interaction between these genes. Furthermore, we will determine the effects of PARK2/FBXW7 disruption on clinical outcomes and genetic stability in primary malignant gliomas. In Aim 3, we will define in knockout mice, the role of Park2 in oncogenesis. Using mouse models, we will characterize the effects of Park2 loss on cancer formation. We will (1) use the RCAS-TVA system, a well-established mouse model of glioma, to determine how Park2 loss specifically modulates glioma formation and pathogenicity, and (2) characterize the effects of Park2 knockout on cancer formation using a carcinogen model and a Park2 -/- p53 -/- mouse model.